Over the past decade it has become accepted that some T cells play a role in dampening down immune responses. These cells are dubbed regulatory T cells or Treg for short. In lab studies, Treg have been shown to suppress the activation of other T cells, and there is considerable evidence that this regulatory function is also performed in vivo. One problem, however, is that there are no definitive markers for Tregs. Initially, expression of a molecule called CD25 was used to define Treg, but CD25 can also be upregulated by other activated T cells. More recently, a transcription factor, Foxp3, has emerged as a more specific marker for Treg. Although several studies have explored the role of Treg in HIV infection, results have been inconsistent and hard to interpret because approaches to define the cells have varied. A new study in the journal AIDS Research & Human Retroviruses uses the combination of CD25 and Foxp3 to explore whether Treg levels differ in individuals with varying rates of disease progression.
Weiwei Cao and colleagues from UCLA employed a case-control approach to compare twenty fast progressors from the Multicenter AIDS Cohort Study (MACS) to forty matched slow progressors and nine uninfected individuals. Fast progression was defined as an AIDS diagnosis within 4 years after enrollment into MACS, whereas slow progressors were categorized based on the absence for an AIDS diagnosis for at least 8 years after entry into the cohort. Treg constituted 4.6% of CD4 T cells in uninfected study participants and this proportion was only slightly increased to 5.6% in slow progressors. Among fast progressors, however, the proportion of Treg was significantly higher at 11.3%. Further analysis showed that Treg levels correlated with CD4 T cell activation; the proportion of CD4 T cells expressing the activation marker CD38 was 1.5% in uninfected individuals, 7.2% in slow progressors and 16.3% in fast progressors.
In the discussion section of the paper, Cao and colleagues suggest that these two phenomena may be linked, because other studies have shown that T cell activation can lead to the generation of Foxp3-expressing Treg from resting T cells that previously did not express the marker. Therefore it is possible that the persistently elevated levels of T cell activation in HIV infection leads to the observed accumulation of Tregs. Some researchers have suggested that immune activation in HIV infection is caused by a lack of Treg, but Cao and colleagues note that their data appears incompatible with this possibility. Rather, their data argues that Treg either have a negative effect – perhaps by interfering with HIV-specific immune responses, as some prior studies have posited – or alternatively the relative expansion of Tregs is just a by-product of immune activation which has no specific role in HIV disease progression.
AIDS Research and Human Retroviruses. February 2009, 25(2): 183-191. doi:10.1089/aid.2008.0140.
Regulatory T Cell Expansion and Immune Activation during Untreated HIV Type 1 Infection Are Associated with Disease Progression (free access to full text PDF)
Weiwei Cao,1 Beth D. Jamieson,2 Lance E. Hultin,1 Patricia M. Hultin,1 and Roger Detels1
1Department of Epidemiology, School of Public Health, University of California, Los Angeles, California 90095.
2Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine, University of California, Los Angeles, California 90095.
Abstract
Regulatory T cells (Tregs) may play an important role in the immunopathology of chronic HIV-1 infection due to their potent suppressive activity of both T cell activation and effector function. To investigate the correlation between Tregs and immune activation during untreated chronic HIV-1 infection, we conducted a nested case–control study within the Multicenter AIDS Cohort Study (MACS). Twenty HIV-1-infected fast progressors (FP) and 40 slow progressors (SP) were included in our study using risk-set sampling. Nine age-matched HIV-1-uninfected men (UI) were also included. Cryopreserved peripheral blood mononuclear cells (PMBCs) were tested using flow cytometry analyses. We identified Tregs as Foxp3+CD25+CD4+ T cells and assessed the activation of CD4+ and CD8+ T cells by the expression of CD38, HLADR, or both markers simultaneously. There is a relative expansion of Tregs during HIV-1 infection, which is associated with disease progression. The increased CD38 expression on both CD4+ and CD8+ T cells expressed as either percentage or median fluorescence intensity (MFI) and the elevated proportion of CD8+ T cells that is HLADR+CD38+ were all associated with rapid HIV-1 progression. Counter to the assumed role of Tregs as the suppressors of activation, the expansion of Tregs was positively correlated with CD4+ T cell activation among HIV-1-infected fast progressors. The high level of Tregs associated with rapid HIV progression may suggest a detrimental role of these cells in the immune control of HIV-1 infection.
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